Phenylquinolinecarboxylic acids are disclosed as antitumor agents in coassigned U.S. Application Ser. No. 727,808 filed Apr. 26, 1985, now U.S. Pat. No. 4,680,299 granted July 14, 1987. These agents are also described in EPO Published Application No. 0133,244, published Feb. 20, 1985. However, in order to avoid contamination or risk from spillage or aerosol inhalation during ampul opening, a freeze-dried powder is a preferred dosage form for these agents.
To prepare a freeze-dried product, it is required to make up a drug solution which can be filtered, filled into suitable containers, and lyophilized to form an elegant cake. Also, after being reconstituted, the drug solution should be free of particulates and be ready for intravenous administration.
The phenylquinolinecarboxylic acids, when in acid form, are insoluble in water. The solutions prepared with the salts of the acids are unstable and have a tendency to form precipitates after a short period of time. Precipitation occurs even at a concentration as low as 100 .mu.g/ml while a solution up to 125 mg/ml is needed for product preparation. It is apparent that solubilizers which can enhance the solubility of these phenylquinolinecarboxylic acids are needed.
Solubilization techniques are known in the art, but such techniques depend on the drugs being formulated. For example, using a co-solvent or a complexation agent for drug solubility enhancement was found useful in some pharmaceutical applications. Such examples can be found in "Techniques of Solubilization of Drugs", edited by S. H. Yalkowsky, Chapter 3, page 91. However, these techniques are not practical for preparing freeze-dried compositions that are reconstituted to intravenous products. For example, co-solvents such as ethyl alcohol, benzyl alcohol and propylene glycol can solubilize a drug to a desirable concentration, but due to the liquid nature of these co-solvents, preparation of freeze-dried powders with these co-solvents is difficult. Attempts to use a complexation agent such as niacinamide up to a physiologically acceptable concentration with phenylquinonecarboxylic acids fails to prevent the acids from precipitation.
Another procedure which has been used to improve the solution stability with some drugs is to use micellar solubilization techniques with suitable solubilizers. However, to identify a useful solubilizer is a challenging task for parenteral formulators because the micelle from each solubilizer behaves differently. For example, the micelles formed from some commonly used solubilizers such as Tween.RTM.20, Tween.RTM.80, and Emulphor.RTM.719P and Pluronic.RTM.F-68 do not have enough solubilization capacity to prevent the quinolinecarboxylic acids from precipitating. Also, incorporating these solubilizers in the parenteral formulation can either result in a change in drug activity due to the inclusion of the drug into the hydrophobic micellar core or cause toxicity to increase due to the surface activity of these solubilizers.
U.S. Pat. No. 4,478,829, issued Oct. 23, 1984, describes the use of bile salts as surface active agents, in the same category as the Polysorbates, Triton.RTM.X100 and Pluronic.RTM.F-68 surfactants, in the preparation of lyophilized fibronectin which is readily reconstitutable with sterile water. Similarly, the bile salt sodium desoxycholate is described in published European Patent Application No. 141922-A1 in combination with freeze-drying to reduce turbidity in reconstituted clinical control sera.
U.S. Pat. No. 4,036,954, issued July 19, 1977, describes the use of a salt of desoxycholic acid as an addition in the lyophilization of a prostaglandin E group compound.
It is known that the freeze-drying technique can be used to convert a drug formulation from an aqueous mixture into a solid form. It is surprising to find that in this invention the antitumor phenylquinolinecarboxylic acid compounds can be successfully formulated into stable aqueous injectable compositions by employing a specially selected type of solubilizer in conjunction with the freeze-drying technique.